1, 2, 4-tribromo pregnane-17alpha, 21 diol-3, 11, 20 trione-21-acetate



United States Patent 1,2,4-TRIBROMO PREGNANE-1'7oz,21 DIOL-3,11,20 TRIONE-Zl-ACETATE Edward W. Tristram, Cranford, N.J., assignor to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Application August 5, 1955 Serial No. 526,773

4 Claims. (Cl. 260-39745) This invention relates to the preparation of 1,4-pregnadiene-l7u,2l-diol-3,l1,20-trione. It is also concerned with the preparation of the novel chemical compounds 1,2,4 tribromopregnane l7a,21-diol-3,l1,20-trione-2lacetate and 4-bromo-l-pregnene-l7a,2l-diol-3,l1,20-tri one-2l-acetate produced as intermediates in the synthesis of 1,4-pregnadiene-l7a,2l-diol-3,11,20-trione. The invention also relates to 2-bron1o-1,4-pregnadiene-l7u,21-diol- 3, 1 1,20-trione-2l-acetate.

The 1,4-pregnadiene-l7a,2l-diol-3,11,20-trione with which this invention is concerned possesses marked and effective properties in the treatment of arthritic conditions. One of the chief disadvantages encountered in the clinical use of hydrocortisone and cortisone has been the retention of sodium and water in the body. In contrast with this, the retention of sodium and water in the body is markedly reduced when 1,4-pregnadiene-17a,21- diol-3,ll,20-trione is administered.

In preparing 1,4-pregnadiene-17a, 2'l-diol-3,ll,20-trione in accordance with the present invention, the starting material l-pregnene-17a,2l-diol-3,1 1,20-trione-21-acetate which has the structure- CIHQOAC is reacted with two molar equivalents of bromine to form 1,2,4 tn'bromepregnane-170:,21-di0l-3,1'1,20-trione- Zl-acetate having the structure-- I 6 The latter compound is reacted with sodium iodideto Patented Sept. 15, 1959 form 4-bromo-l-pregnene-l7u,2l-diol-3,l1,20-tri0ne-21- acetate having the structure-- The latter compound is reacted with an organic base in the presence of lithium chloride to form 1,4-pregnadiene-17u,2l-diol-3,1l,20trione-21-acetate having the following structure- ([lHaOAc The organic bases which may be employed in this re action include dimethylformamide, collidine and dimethylaniline.

The 1,4-pregnadiene-l7a,21-d.iol-3, l 1,20-trione-2l-acetate may be hydrolyzed to form l,4-pregnadiene-l7a,2jldio1-3,11,20-trione.

Alternatively the 1,2,4-tri-bromopregnane-17a,21diol- 3,11,20-trione-21-acetate can 'be reacted with an organic base in the presence of lithium chloride to form Z-bromo- 1,4-pregnadiene-17a,2l-diol-3,1 1,20-trione-21-acetate having the structure- GHzOAc The preparation of 1,4-pregnadiene-17u,21-diol-3,11,

-trione can be indicated graphically as follows:

n Or g To a solution of 5.0 grams (12.5 millimoles) of 1- Zpregnene-17u,21-diol-3,11,20-trione-21-acetate in 250 ml.

of glacial acetic acid at room temperature was added with stirring over the course of five minutes 4.0 grams millimoles) of bromine in 17 ml. of acetic acid. The

1,2,4 tribromopregnane 1711,21 diol 3,11,20 trione- 21-acetate thus formed can be isolated as described in Example 2. In the present procedure, however, the 1,2,4- tribromopregnane-lhl1-diol-3,11,20-trione-21-acetate is not isolated from solution. After stirring for ten minutes, to the clear yellow solution containing 1,2,4-tribromopregnane l7a,21 diol 3,11,20 trione 21 acetate was added 3.75 grams (25 millimoles) sodium iodide dissolved in ml. of acetic acid for five minutes. The solution was diluted with 250 ml. of water and 0.1 M sodium thiosulfate solution was added dropvvise with stirring until the iodine color was discharged. A total .of 225 ml. (90%of theory) of thio sulfate solution was required. An additional 500 ml. of water was added .dropwise with stirring and the slurry was then cooled in the ice bath for one hour. The product 4-bromo-1- pregnene-17u,2l-diol-3,11,20-trione 21 acetate was filtered, washed with water and dried under vacuum.

Light yellow crystals of 4-bromo-l-pregnene-17u,21-

diol-3,11,20-trione-21-acetate were obtained. These crystals had a A maximum 2220 A., E% 143 in methanol. Analysis.Calculated for C H O Br: Br, 16.6. Found: Br, 17.1. A sample recrystallized from methanol contained 16.8% bromine, [a] +163 in chloroform. A maximum 220, E% 160.

Two grams (4.1 millimoles) of 4-bromo-1-pregnene- 17u,21-diol-3,11,20-trione-21-acetate was added to 0.5 gram of lithium chloride in 20 ml. of dimethylformamide omoAc and the reaction mixture heated on a steam bath for two hours. The clear solution was diluted with 20 ml. of water while hot and allowed to cool to room temperature over a two-hour period. A crystalline product 5 separated from solution and was recovered by filtration.

The crystals were washed with 10 ml. of 50-50 waterdimethylformamide and then with water. After drying under vacuum the crude crystals of 1,4-pregnadiene- 17a,21-diol-3,11,20-trione-21-acetate had a melting point 10 of 220230 C. A maximum 2640, E% 366 in sulfuric acid, A maximum- 2390, E% 356 in methanol.

1,4 pregnadiene 17a,21 diol 3,11,20 trione-21- acetate can be readily converted to 1,4-pregnadiene- 17a,21di0l-3,11,20t1i01'1e by hydrolysis of the 1,4-pregnadiene-17a,21-diol-3,l1,20-tri0ne-21-acetate in an oxygen- (IJH OAc 0:0 '----011 free atmosphere with sodium methoxide in methanol for a period of about seven minutes at room temperature.

Example 2 Preparation of Z-bromo-1,4-pregnadiene-17a,21-diol- 3,11,20-trione-21-acetate can be graphically indicated as follows:

n 1:1 .m an

OH OAG One gram (2.5 millimoles) of 1-pregnene-17a,21-diol- 3,11,20-trione-21-acetate in 50 ml. of glacial acetic acid was treated with 0.8 gram (5.0 millimoles) of bromine over the course of five minutes. After stirring at room temperature for twenty minutes the reaction was quenched with 200 ml. water. After standing for one hour the product was filtered, washed with much water and dried under vacuum. A methanol solution had no absorption maximum in the ultraviolet.

A solution of 1.24 grams (1.9 millimoles) of 1,2,4- tribromopregnane 1701,21 diol 3,11,20 trione 21- acetate and 1.2 grams of lithium chloride in 12.5 ml. of dimethylformamide was heated on the steam bath for two hours. The hot solution was diluted with an equal volume of water and allowed to cool to room temperature. The solid was filtered ofi, washed with water, and dried under vacuum to give crude 2-bromo-1,4-pregnadiene- 17u,21-diol-3,11,20-t1ione-21-acetate, maximum 2480 A, 13% 260 in methanol.

Any departure from the above description which conforms to the present invention is intended to be included within the scope of the claims.

What is claimed is:

1. 1,2,4 trigromopregnane 170;,21 diol 3,11,20- trione-21-acetate.

2. The process which comprises reacting 1-pregnene- 6 17a,21-(1i013,11,20 trione 21 acetate with two molar equivalents of bromine to form 1,2,4-tribromopregnane- 17a,21-diol-3,l1,20-trione-21-acetate, and reacting the latter compound with sodium iodide to form 4-bromo-1- pregnene- 17u,21-diol-3,l 1,20-trione-2l-acetate.

3. The process which comprises reacting l-p-regnene- 17a,21-diol-3,11,20-trione 21 acetate with two molar equivalents of bromine to form 1,2,4-tribromopregnane- 17 ,2 1-dio1-3,1 1,20-trione-2 l-acetate.

4. The process which comprises reacting 1,2,4-tribromopregnane 1704,21 diol 3,11,20 trione 21 acetate with sodium iodide to form 4-bromo-l-pregnene-17a,21- diol-3 ,1 1,20-trione-2 l-acetate.

References Cited in the file of this patent UNITED STATES PATENTS 2,590,978 Kendall Apr. 1, 1952 2,703,805 Rosenkranz Mar. 8, 1955 2,730,537 Nathan Jan. 10, 1956 2,735,855 Djerassi Feb. 21, 1956 2,737,518 Herzog Mar. 6, 1956 

1. 1,2,4 - TRIGROMOPREGNANE - 17A,21 - DIOL - 3,11,20TRIONE-21-ACETATE. 